Cardiovascular diseases and dyslipidemia disorders are currently recurring conditions for which there are different drugs such as statins, fibrates and combinations thereof.
Rosuvastatin, a pyrimidin derivative, is an inhibitor of 3-hydroxy-3-methylglutaryl coenzime A (HMG-CoA) reductase, which catalizes the conversion of HMG-CoA to mevalonate, limiting initial step of cholesterol biosynthesis. It has a relative hydrophilic capacity. Its metabolism is independent of Cytochrome P450 (CYP), presenting less pharmaceutical interactions than atorvastatin and simvastatin.
Rosuvastatin is mainly used as calcium salt (formula I). This salt has an absolute bioavailability of approximately 20%, it binds to proteins in an 88%, reaching a maximum peak between 3 and 5 hours. It is mainly excreted in feces (90%) and urine (10%), with a half-life of 19 hours.

Rosuvastatin is slightly soluble in water, not very stable in extreme environmental conditions, is a compound with acidic characteristics, therefore it is mainly associated to compounds with alkaline characteristics such as metallic salts of calcium, zinc, strontium, sodium, magnesium, lithium, among others. It can be seen from different publications on rosuvastatin that problems arise during the synthesis process to obtain rosuvastatin salts and during purification and crystallization processes. From the above it is displayed that the problem of obtaining stable salts, that may be used for producing physicochemically stable compositions, has not been solved.
U.S. Pat. No. 5,260,440, (USRE37314-Shionogi) describes the synthesis of (3R,5S,6E)-7-[4-(4-fluorophenyl)-2-(N-methyl methanesulfonamide)-6-(propan-2-yl)pyrimidin-5-yl]-3,5-dihydroxihept-6-enoic acid, commonly known as rosuvastatin. This patent describes a complex process for obtaining rosuvastatin with diastereoisomeric impurities. In contrast, in this invention a new salt of rosuvastatin with improved stability and solubility properties without diastereoisomeric impurities is obtained.
International application WO2000/042024 describes processes for obtaining amorphous rosuvastatin, where rosuvastatin impurities are obtained in lower amount, in comparison to the process disclosed in U.S. patent '440. Unlike in this invention, the process of application WO2000/042024 is characterized by a purification method for rosuvastatin to obtain calcium rosuvastatin, and rosuvastatin is not in the form of an amino acid salt, as is the objective of the present invention.
WO2001/060804-ASTRAZENECA (Mexican Application PA/a/2002/000781, U.S. Pat. No. 6,841,554) describes the preparation of crystalline salts of rosuvastatin in order to solve technical problems of the process disclosed in U.S. Pat. No. 5,260,440. These crystalline salts are more easily purified in comparison to an amorphous form, they are more physicochemically stable and more resistant to oxidative degradation. This document mentions the development of rosuvastatin salts of ammonium, methylammonium, ethylammonium, diethylammonium, tris(hydroxymethyl)methylammonium, benzylammonium, 4-metoxibenzylammonium, lithium or magnesium salt. This document refers to stable salts where the anion is a metal or an ammonium compound, unlike the present invention which refers to stable salts with amino acid.
ASTRA's WO2004/014872 (Mexican Appl. PA/a/2005/001582, U.S. Pat. No. 7,511,140) describes the preparation of a rosuvastatin calcium salt that demonstrates effectiveness in its synthesis process, particularly in the filtration step, characterized in that a calcium chloride salt is mixed with a solution of rosuvastatin sodium salt soluble in water. This is an improvement in the process of obtaining the rosuvastatin calcium salt, however the described salt do not correspond to the salts of the present invention.
TEVA's U.S. Pat. No. 7,582,759 (Mexican Application MX/a/2007/037979, WO2006091770, EP1737829), describes the preparation of rosuvastatin intermediaries and salts thereof, it comprises the use of an alcohol of the methanol kind, with an organic solvent and an hydride ion source. A pure enantiomeric salt of rosuvastatin is obtained, excluding salts formed with amino acids.
MX/a/2007/009281—Lifecycle Pharma A/S (WO06084474, US2008131503), presents an oral composition comprising a mixture combining fenofibrate and a HMG-CoA reductase compound, in separate entities in a single dosage form. HMG-CoA reductase is a statin selected from the group of atorvastatin, lovastatin, pravastatin, simvastatin, rosuvastatin, fluvastatin and pitavastatin, being atorvastatin the preferred one. Unlike this formulation, the present invention provides a rosuvastatin stable salt with improved solubility, as well as its method of synthesis and obtention thereof.
WO06126035-Richter Gedeon Vegyészeti Gyár Rt. HU (EP1902036B) refers to a rosuvastatin calcium preparation process starting from (6-{(E)-2[4-(4-fluorophenyl)-6-isopropyl-2-(methanesulfonyl-methyl-amino)pyrimidin-5-yl]-vinyl}-(4R,6S)-2,2-dimethyl-[1,3]dioxan-4-yl) acetic acid, which may preferably presented as salt formed with diethanolamine, L-lysine or magnesium. These salts are reacted with calcium chloride in the presence of an alkali to remove the acetonide group and to obtain calcium rosuvastatin as final product. Unlike this formulation, the present invention provides a process for obtaining a rosuvastatin lysine salt instead of the rosuvastatin calcium salt without starting from an intermediary and in a shorter time than the synthesis process described in the patent WO06126035.
WO07089745—Signature R & D Holdings Llc (U.S. Pat. No. 7,589,233), refers to a method for improving at least one therapeutic property of an active ingredient by combining an amino acid and an active ingredient. Compositions preferably may be the combination of a L-threonine derivative and an active ingredient selected from different therapeutic groups, one of which groups can be rosuvastatin, resulting in the physical combination of threonine and rosuvastatin. The present invention relates to the synthesis of a rosuvastatin lysine salt, where the salt thereby obtained has better solubility and physicochemical stability properties, and is useful for preparing a medicament.
WO2006/136407 Lek Pharm. (US2009111839, EP1912952A) describes a process for preparing a pure form of amorphous rosuvastatin with a purity ranging from 99.5% to 99.9%, wherein the process is carried out through hydrolysis of C1-C5 of the rosuvastatin alkyl ester, preferably rosuvastatin tert-butyl ester with a nitrogenous base such as guanidine, amidine, amines and quaternary ammonium hydroxides in the presence of water or an aprotic solvent.
Rosuvastatin in its basic form and amorphous rosuvastatin salts are very unstable and slightly soluble in aqueous solutions, therefore it is an objective of this invention to present a rosuvastatin salt with improved solubility and stability properties. There are different rosuvastatin salts as well as new purification processes of these salts. The existing salts of rosuvastatin are basic salts and mineral salts such as magnesium, lithium, aluminum, zinc, strontium, among others, and can be amorphous or non-amorphous salts. Their manufacture methods occur through complex processes with organic solvents, filtration, drying, re-crystallization processes and others that increase operating time as well as their manufacture cost.
The present invention provides a new rosuvastatin salt which is more stable and more soluble than the available rosuvastatin salts, for the elaboration of pharmaceutical compositions.
Justification of the Invention
For the production of rosuvastatin salts with magnesium, lithium, aluminum, zinc, strontium and calcium there are different processes that, to date, still have the problem of rendering diastereoisomeric impurities, besides they present solubility problems during the elaboration of pharmaceutical forms. Therefore, there is a need of a process for obtaining a rosuvastatin salt with less by-products, wherein the salt is stable for preparing a pharmaceutical composition which is physicochemically stable and useful for treating cardiovascular diseases.
The present invention provides a rosuvastatin amino acid salt with improved aqueous solubility and more physicochemical stability, which provides more absolute bioavailability and improved pharmacokinetics when preparing a pharmaceutical composition.
However, it is not possible to obtain this salt by simple association of rosuvastatin with any amino acid, since particular conditions must be created during the production process, such as selecting appropriate raw materials, atmosphere, temperature, moisture, pH; an example of this situation, contrary to what might be expected, is that it is not possible to produce the salt with arginine.
The present invention comprises a rosuvastatin salt with an amino acid that can be lysine or histidine, in a non limiting way.
The rosuvastatin salt of this invention can be obtained with good yield and good purity, so that it is specially suitable for the manufacture of pharmaceutical formulations.
The rosuvastatin lysine salt of this invention offers better flowability compared to the calcium salt. This property provides better conditions for preparing a pharmaceutical composition.
In the solubility assay, the rosuvastatin-lysine salt of the present invention exhibits a greater and better aqueous solubility, being of 218 mg/mL versus 5.3 mg/mL of rosuvastatin calcium, which represents an increased solubility by just over 40%. This property allows it to be more bioavailable within the organism when being presented in pharmaceutical compositions.